Method of preparing diphenyl acetic acid



Patented Aug. 8, 1950 NJITE'D 5S '1 PAT EN T v O FFI'CE.

- 2,517,856 METHOD (TFPREPARING DIPHENYL ACETI-G' ACID Herbert R.llllkir t'on,v Orangeburg, George Kesslin, New ilork and Leonard Nicholl, Nyack','-=N. Y4

' assignors to lKay Fi-ies Chemicals, Inc., West Haverstraw,,'N. Y.,' a corporation of New York No Drawing. =LApplication May 12, 1949, Serial N 0. 92,968

This invention relates '--toimprovements in methods of preparing diphenyl acetic-acid, and, more particularly, tostheuse of chloral asas-basic starting material with -theoptional formation of diphenyl- "trichlorethane, 'or glyoxyllc acid as intermediate compounds, which -.-are separately elaborated to form diphenyl acetic acid.

:Diphenyl aoetic acid isanimportant intermediate or starting compound for the preparation of a number of spec'ia-l chemicals having-particular utility as :bacteriostatsin'the treatment of malariaand like diseases.

The methods available forithepreparation of diphenyl acetic acid are-costlyandtime-consuming, as well as requiring. special, --.-high priced chemicals, which are in relatively short supply. Among these prioriai tvchemicalswhich have been used for starting materials are benziLi be'nzoin, andidip-henyl methane.

When benzil is used, it is heated-ii n strongzsm dium hydroxide toiform-ibenzilic acidssodiumsal-t, which is acidified 'vvith hydrochloric acid-to-iorm benzilic acid. The latter compound isareactedwin giacialaoetic acid solution, with phosphorous and iodine as catalysts, to give diphenyl aoeticiacid.

When using benzoin as a. startings material;the benzilic acid-sodium salt is -formed-=by-reacting benzoin and sodium broma'te in strongly alkaline solution; The "sodium salt is acidified with hydrochloric acid to formnlaenzi'lic'iacid,which is reacted withiphospho'rusiand iodine'r in glacialiadetic acid solution to give diphenyliaeeticfiacidl In the use of diphenyl methane-this compound is first prepared by 'reacting benzene andibenzyl chloride in the presence of aluminum-chloride. The diphenyl methane -is reacted with sodium .phenyl to give diphenyl methyl sodium and benzene.. The diphenyl methyl sodium is recovered an'd'carbonated with carbon dioxide td'gi-ve idiphenyl acetic acid sodium salt, whichis. acidified with hydroehloric acid to give diphenyl acetic acid.

Considering the procedures. outlined abovegit' i's noted that withbenzil, strong causticis-usedand with benzoin, strong caustic :andsodiumibromate are used. .Noneof these., procedures-are conveniently carried out on a- -practical,commercial scale. Additionally, the reductionof-benzilicacid inglacial'acetic acid solution, usinglphosphorous difficult to handle under any conditions, and the organo-metal compound, diphenyl methyl sodium is not conveniently worked with.

The available procedures of the prior art are industriallyimpractical, 'as well, from technical grounds, as from the standpoint of high cost of starting materials, equipment and time.

It has now been found that the prior art dimculties in the preparation of diphenyl aceticacid on a commercial scale can be essentially overcome by the improvements of the present invention, which involve the use of chloral as a=basic starting material from which-diphenyl trichlorethane can be prepared, and elaborated to form the diphenylacetic acid. In the case of diphenyl trichlorethane,"it is hydrolyzed with caustic soda, the reaction being carried out in a special solvent, to form the sodium salt of diphenyl acetic acid. which is recovered and acidified.

It:is,.thereiore,among the features of novelty andadvantage 01' the present invention, to provi'd'e .novel methods for the preparation of dip'henyl acetic acid using chloral as. a basic starting material, and utilizing intermediates prepared therefrom, including diphenyl trichlorethane-.-prepal'ed directly Irom the chloral, and treated :-to secure the desired diphenyl acetic acid.- 7

A- -iurtherieature-of novelty and advantage of --the .present invention includes the special treatment of diphenyl trichlorethane in diethylene glycohsolution with caustic soda, and s t-atmospheric :spressure, to form the diphenyl "acetic acid sodium sait which :is recovered and and iodine, not only. commercially diflicult, but -50 acidified 'toogive the diphenyl acetic acid. -Oth'er features of novelty and advantage inelude the use-of chlorsulphonic acid as a re.-

acta-nt; the carryingnout of multiple reactions in one step; the elimination of the requirement -forw'm' king under pressure; and a marked'reduction of the reaction time.

Considering the -.improved methods herein, the preparation of diphenyl acetic acid from chloral will' be described with reference to the formation and use of diphenyl trichlorethane as an intermediate compound. The reactions involved include the following:

H @0001, 4NaOH (Diphenyl trichlorethane) (Diphenyl acetic acid sodium salt) H NaO 6-0 0 0N8 +1101 Theory yield-856 gms. diphenyl trichlor ethane diphenyl trichlorethane.

Actual yield-816 gms. diphenyl trichlorethane (95.4% yield).

ProceduTe.--The chloral and benzene are loaded into a 2 liter, B-necked flask, mounted in a water bath and equipped with agitator, reflux condenser, thermometer and addition funnel. CISOxI-I is added to the reagents, over a period oi, one :hour and ten minutes, while .the reactionmixture is held at a temperatureof -30 C. After the addition of the chlorsulfonic acid is completed, the temperature of the reaction mixture is allowed to rise to and held there,

by intermittent cooling, for another hour. The reaction mixture is then heated to 50-55 C.,

and held within this temperature range for a three hour period. The reaction mixture separates into two layers: a bottom, sulphuric acid layer, product layer.

and an upper, supernatant benzene- The sulphuric acid layer (lower) is drawn off, leaving the supernatant benzene- (Diphenyl acetic acid sodium salt) ently because f the fact the diphenyl- .tri-

chlorethane'is not soluble therein. .The.unique and hitherto unexplained behavior ofdiethylene glycol will be more full appreviated. by..reerence to the tables hereininwhichthe. results of using other alcohols, under identical condi; tions with diethylene glycol, are more fullyset out.

The preparation of the diphenyhacetic acid is carried out as follows: H

Step I.Condensation Materials- 774 gms. C1SO3H (6.6 Inols) (430 cc. 655 gms. benzol' (8.4 mols) 10% excess; 496 /2 gms. chloral 3 mole);

Occooa+mo1 Glycerol is foundto be wholly and the D'IE'loaded in' all at once. ti'on mixture'is heated to reflux temperature (approximately160 -C.)-, and maintained at 155- "160-'C:,*for"aperiod of nine hours, to formdi- "phe'n'yl acetic a'cidsodium salt. Intermittent removal'of water may be necessary'to keep the "liquid-temperature"at "155*t0 160 -C.' At the end-"of this period the reaction mixture is diluted prpductlayer, which is loaded into a 2 liter fiask"('1900 cc. Water added), and the benzene distilled off. 400 gms. of NaCl is added to the residue (diphenyl trichl'orethane) in the flask, and the mixture heated to 60-70" C. to melt the diphenyl' trichlorethane. On cooling, with agitation, the DTE comes down in medium size granules that are easily filtered and washed. The filter cake is washed well with water to remove as much acid as possible. An alternative method for isolating the product would be toseparate the product layer from the water after heating to Gil- C., and allow the diphenyl trichloretha'ne to solidify. An analysis of the diphenyl trichlorethane is required for use in the following step.

4 Resultse- -weight of diphenyl trichlorethane made, 816 gms., 95.4% yield.

Ste'p II.Hy'droZysis 285.5 gms. diphenyl trichlorethane (from step I after'drying);

748 gms. (6'70 cc.) diethylene glycol.

:219' gms. 97.3% NaOI-I-5.33 mols.

1000 cc. 'water.

260 gms. of 35% -I-ICl (220 cc.) or the equivalent amount of H2804.

1450 gms. water.

v300 cc. solvent naptha (B. P. 200 C.)

5 .gms. activated carbon.

412 gms. 97.3 NaOI-Ipercent (equivalent to the originaldiphenyl acid).

101.5.gms}, (85.8 cc.) 35% HCl, or the equivalent amount of H2SO4.

Theor ji/ieldma gms. diphenyl acetic acid. Actual yield-148.5 g. diphenyl aceticacid=approximately 74.5% of 99% diphenyl acetic acid- "Procedurei The NaOH and diethylene glycol areloaded'into a '2 liter 3-necked flask, equipped with agitator, thermometer and reflux condenser. The mixture is heated to C; to eifect soluticriof the 'NaOI-Iin the diethylene glycol. The

resulting solution is then cooled to about 100 C.,

This reac- Solvent lizessnre 'mieth'yleneIIGlycoL TriethylenaGlycoL. butyl ether ofethylen lveol Reagents used.-In Examples 1-8, 61.8 g. of 'wondenser, ithermometer,'s'addition siunnel, sand 85% KOH was added to 300 cc. solvent and 42.9 g. exhaust line from the condenser to carry away diphenyl trichlorethane was added after solution 60 evolved HCl. The CISOaH' is added over a one was effected. Exception as noted. In Examples hour period, the reaction mixture being held at 9-13, 49.5 g. of 97.3% NaOI-I was added to 300 cc. 3. temperature of 25-30 C. After addition of solvent and 43.0 g. diphenyl trichlorethane was ,the ClSOaH is completed ,fthe temperature of the added after solution was effected. Exceptionsas flgieaction b th is allowed t rise (spontaneously) noted: 65 to 3540 0., being held there, with intermittent (a) g. of 85% KoHand 223 g diphenyl cooling, for another hour. It is then brought up trichlorethane were added to 300 cc. solvent due heated another to low solubility of KOH in N butano1 Total reaction time 3 hours. Upon completion (b) of 359% KOH and 355 ip Of the reaction, 3'7 g, H2O is added slowly to the trichlorethane were added to 500- cc. solvent. 7 mixture. to dilute the H2804 f reaction to a u (0) 56.5 g. of 85.0% KOH and 36.0 g. diphenyl Cool w be ec ssa y to ep he temtrichlorethane were added to 400 cc. solvent. Not Denture between and 5 e b c all of KOH was in solution. weight at this point is about 735 g., the volume (d) 67.0 g. of 97.3% NaOH and 59.7'g.dipheny1 being 560 cc. The reaction mixture then sepatrichlorethane were added to 300' cc. solvent. rates into two layers, a bottom acid layenand 9. supernatant benzene-product layer .Thelacid layer is drawn off and the excess benzene, is, then stripped off from the residuum,: undenthe best vacuum possible (-40 mm.) at a'maxirnum liq,- uid temperature of C. ,215,g, benzeneis then added to the residual batch and agitated to insure a uniform mixture Moreacidis allowed tosettle out and is separatedoii from. the benzene solution of diphenyl trichlorethane. j

Results.Weight of diphenyl trichlorethane solution-624 g. Analysis, diphenYltrichloretha'ne 65.0%; acid .'2".3%. Yield' of" diph'enyltrtchlor'ethane-405 g; or 95.0%; Step II .-Hydrolysis- Materials.-- v 285.5 gms. diphenyltrichlorethane solution inbenzene). M I 748 gms. (670 cc.) diethylene glycol. f- 2 19;gms.97.3%'NaOH (33 /3% excess).

1000, cc. H20 for 1.5 1 dilution.

Procedure.The NaOH and diethyleneglyc'ol 'areldaded into a two liter Ii-necked flask equipped with thermometer, addition tunnel, emcient ia tator, distilling column with cold spot mother device to control the take off. The mixture isheated to 155 C., and then the diphenyl trichlorethane solution is started in. I Benzene and water will distill out, The rate of addition, heat input, and rate of distillation, are balanced so that the addition takes about one hour, and the liquid temperature is maintained between 155-160? C.

The batch is then refluxed for 5 hours after addition of the reagents is completed; Upon completion of the reaction, the reaction mixture is diluted with 1000 cc. of water andicooled. It is then acidified, the crude diphenyl acetic acid filtered off, and washed well with water. About 750 to 1000 cc. of water should be used on the wash, the first 150 to 200 cc. of wash Water being added to the mother liquor, and the remaining 8 to determine if git is; still alkaline. If not, more caustic mustbe added. qThewater solution of the sodium salt of theacid is then extracted with three 150 ,-cc. ,portions of benzene. After the thirdextraction, activated carbon is added, and the -mixture, blown with air, at Ski- ,C., for about one half hour to one hour, to remove residual benzene from the washes. The activated carbon is then; filtered oil, the water solution acidified' with ,H2SO4,'; under agitation, and cooled. The diphenyl acetic acid is filtered oil and washed with waterv and dried.

.Results.Weight of diphenylacetic acid. made: approx. g. (99.5% pure or better). 1.5

Itwill now beappreciated that there have been disclosed novel methods for the preparation, of

,diphenyl acetic acid from chloral as a basic starting agent, ,andwhich methods include, inter alia, thepreparation of diphenyl trichlorethane as an intermediate, which is dissolved in diethylene glycol. solution ofcausticsoda, .and reacted at 150- C., at atmospheric pressure, for a relatively short period, to hydrolyze the diphenyl trichlorethane. to the sodium salt of diphenyl acetic acid, whichisseparated, and then acidified, to give the desired end product, diphenyl acetic acid in pure form and high yield.

What is claimed is:

1. The method of hydrolyzing diphenyl triychlorethane to form the alkali salt of diphenyl .acetic acid, comprising dissolving a unitcharge of diphenyl trichlorethane in an excess of alkali dissolvedin diethylene glycol, and reacting the mixture at 150-155 -C, for a time period Of 4 /2 .hoursand-at atmospheric pressure.

2. The method of hydrolyzing diphenyl .trichlorethane to form alkali salts of diphenyl acetic acid, comprising dissolving a unit charge of 42.9 g.

of DTE in an alkali-glycol solution comprised iiof 61.8 g.:KOH and 300 cc. of diethylene glycol,

and reacting the mixture at 150-455 C., for a time period of .4 /2 hours .and at atmospheric pressure.-

' HERBERT R. ELKINTON.

GEORGE EssLm. LEONARD NICHOLL,

REFERENCES CITED The following references are of record in th file of this patent:

Baeyer, Beilstein (Handbuch, 4th ed.), vol. 5,

washes kept separate and discarded. The wet diphenyl acetic acid filter cake ,(containingabout 30% water) is loaded into 1450 cc. H2O containing 42 g. NaOH and agitated for about one half hour. The solution should be checked at thisltime Harris et al., Beilstein (Handbuch, 4th ed.), 2nd Suppl, vol. 5, p. 510 (1942).

Gatzi et al., Chem. Abstracts, vol. 40, C01. 5040 

1. THE METHOD OF HYDROLYZING DIPHENYL TRICHLORETHANE TO FORM THE ALKALI SALT OF DIPHENYL ACETIC ACID, COMPRISING DISSOLVING A UNIT CHARGE OF DIPHENYL TRICHLORETHANE IN AN EXCESS OF ALKALI DISSOLVED IN DIETHYLENE GLYCOL, AND REACTING THE MIXTURE AT 150-155*C. FOR A TIME PERIOD OF 4 1/2 HOURS AND AT ATMOSTPHERIC PRESSURE. 